JP2014513719A - Rivastigmine-containing patch - Google Patents

Abstract

  The present invention relates to a rivastigmine-containing patch with improved storage stability and suitable release properties.

Description

  The present invention relates to a patch having improved storage stability and containing rivastigmine as an active ingredient.

  This application claims priority based on Korean Patent Application No. 10-2011-0048068 filed on May 20, 2011, and all the contents disclosed in the specification and drawings of the corresponding application are incorporated in this application. The

  Rivastigmine, (S) -N-ethyl-3- [1-dimethylamino) ethyl] -N-methyl-phenyl-carbamate, is used for the treatment of Alzheimer's disease and is acetylcholinesterase in the central nervous system It is useful for suppression.

  Such rivastigmine is commercially available in a patch dosage form. A patch form of the transdermal composition is disclosed in Example 2 of British Patent 2,203,040. Such patches are made by mixing rivastigmine with two polymers and a plasticizer to make a viscous composition and then applying the composition to the foil.

  US Pat. No. 6,335,031 relates to a transdermal composition containing rivastigmine or a salt thereof using an antioxidant as a stabilizer. According to the above U.S. patent, since the transdermal administration composition containing rivastigmine is decomposed by oxidation reaction with oxygen even under sealed storage conditions, it is difficult to secure the storage period necessary for commercial distribution. To solve, a transdermal composition of rivastigmine comprising an antioxidant such as tocopherol and its esters, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, and propyl gallate is disclosed. . Tocopherol is used as a stabilizer in rivastigmine transdermal administration products on the market.

  However, since tocopherol is easily decomposed by air or light, it must be refrigerated and stored in an inert atmosphere, and since it is in a liquid phase, it is difficult to handle and store during commercial production. In addition, since it has anticoagulant action in vivo and there is a risk of bleeding when overdosed, many pharmaceutical licensing agencies limit the usage and absorption of tocopherol.

  Therefore, there has been a need for a rivastigmine patch that solves the above problems and has improved stability.

British Patent No. 2,203,040 US Pat. No. 6,335,031

  The present invention has been made in view of the above problems, and an object of the present invention is to provide a rivastigmine-containing patch preparation with improved stability.

  In order to achieve the above-mentioned problems, the present inventors have conducted many experiments described later in Examples, and have reached the following conclusions.

  First, as a result of studying the drug-containing layer, the following conclusions were obtained.

  The excipient with good compatibility with the main component was selected with reference to the result of the compatibility test, and the permeability due to the concentration of the main component was observed. As a result, the permeation rate equivalent to that of the control drug (for example, It has been found that the concentration of the main component for having a flux is 15 to 35% by weight, preferably 25 to 35% by weight, based on the total weight of the drug adhesive layer after drying. When this formulation is applied to the human skin for 24 hours, a phenomenon occurs in which the adhesive is poorly adhered and the patch slides and moves from the application site, thereby causing a dark ring on the applied skin. It was done. In order to improve it, it was decided to develop a double-layer formulation in which the skin adhesive layer was produced with the main component and another series of adhesives that were not mixed with the acrylic adhesive, and was superposed on the drug-containing drug layer.

  Second, as a result of studying the skin adhesive layer, the following conclusions were obtained.

Of the double-layer formulation of rivastigmine patch, the skin adhesive layer (second layer) using a silicone adhesive acts as a barrier between the skin and the drug adhesive layer, reducing the permeability of the main component. Therefore, the thickness has an important influence on the skin permeation rate of the drug. When the permeability was observed by changing the thickness of the second layer, the formulation having the same transmittance as that of the control drug was bio PSA 7-4202 30 mg / 10 cm ² or Bio PSA 7-4302 based on the weight after drying. The formulation used 30 mg / 10 cm ² as the skin adhesive layer. Bio PSA 7-4302 20-40 mg / 10 cm ² , preferably Bio PSA 7−, similar to the adhesive strength of the control when comparing the adhesive strength of the adhesive, in order to select the most preferred of the two formulations 4302 27-33 mg / 10 cm < ² >, more preferably Bio PSA 7-4302 about 30 mg / 10 cm < ² > formulation was selected as the preferred formulation for the rivastigmine patch according to the present invention.

  Third, as a result of research on polymers, the following conclusions were obtained.

  If the rivastigmine free base, which is the main component of the rivastigmine patch, is in a liquid phase at room temperature and the main component occupies 30% by weight or more of the drug adhesive layer formulation after drying, a thickening polymer is added. Because of the necessity, a study was conducted to set the ratio of a polymer exhibiting a permeability equivalent to that of the control drug using a polymer (PLASTOID B) that is compatible with the main component. Therefore, an experiment was conducted to set the ratio of the polymer by adjusting the amount of the polymer to 10% by weight to 30% by weight relative to the total weight of the drug adhesive layer after drying. As the polymer content increased, the transmittance decreased. I understood that. This is thought to be due to the increase in viscosity with increasing polymer amount, which hinders drug diffusion and drug release, but the present invention is not limited by such theoretical assumptions. Therefore, it was confirmed that the formulation containing 20% by weight of the polymer in the formulation with respect to the total weight of the drug adhesive layer after drying exhibits the most similar permeability as that of the control drug.

  Fourthly, the most desirable final formulation among the many formulations belonging to the present invention selected through a formulation study is shown in Table 1 below.

  In Table 1, the solvent is removed in the drying process. Each content in Table 1 means the weight after drying. That is, Durotak 87-235A and Bio PSA 7-4302 contain a certain amount of solvent other than the polymer in the product itself, but are content values excluding such a solvent.

  After the rivastigmine patch is manufactured with the final formulation selected, it should be comparable to the permeation rate (eg, flux) of the control drug for 72 hours on membrane and human cadaver skin. It was confirmed.

  Fifth, the following conclusions were obtained as a result of the packaging condition selection test.

  A severe stability test was conducted to select packaging conditions for stable storage of the rivastigmine patch. The packaging conditions were divided into air packaging and nitrogen packaging, and the stability of rivastigmine patch was evaluated under severe conditions. As a result, it was confirmed that there was little increase in the flexible material when packing with nitrogen.

  That is, the present inventors, through many studies, appropriately select the pressure-sensitive adhesive and polymer contained in the rivastigmine-containing layer, adjust their content at a specific ratio, and appropriately configure the components of the skin adhesive layer. By selecting, adjusting the thickness, and further packaging the rivastigmine patch according to the present invention by an appropriate packaging method, without using a stabilizer such as tocopherol that contains various problems, The inventors have arrived at a surprising invention that can ensure the stability of rivastigmine and achieve proper release.

Therefore, the present invention
(A) a rivastigmine free base; a copolymer of butyl methacrylate and methyl methacrylate; and a drug adhesive layer produced using an adhesive; and (b) a double layer of a skin adhesive layer comprising a silicone adhesive. In the rivastigmine-containing patch containing
A rivastig comprising a random copolymer of 58 to 66 parts by weight of 2-ethylhexyl acrylate, 28 to 36 parts by weight of methyl acrylate, and 4 to 8 parts by weight of acrylic acid as an adhesive for the drug adhesive layer. Min patch is provided, and more preferably, DURO-TAK ^™ 87-235A (Henkel) is used as the adhesive of the drug adhesive layer.

More preferably, the copolymer of butyl methacrylate and methyl methacrylate contained in the drug adhesive layer is a random copolymer of butyl methacrylate and methyl methacrylate, and has a weight average molecular weight of 130,000 to 170,000 g / mol. Most preferably, PLASTOID ^™ B (manufactured by Evonik) is used as such a copolymer.

More preferably, dimethylsiloxane-treated trimethylated silica is used as the silicone adhesive of the skin adhesive layer, and most preferably BIO-PSA ^™ 7-4302 (manufactured by Dow Corning) as such silicone adhesive. Is used.

Such a silicone adhesive has many effects on the release of rivastigmine depending on the amount used, but as a result of experiments, the BIO-PSA ^™ 7-4302 is 27 to 33 mg / 10 cm ^{2 based on} the weight after drying. It was most desirable to be applied and manufactured at a dose of about 30 mg / 10 cm ^{2 based} on the weight after drying.

The present invention also provides
(A) a drug adhesion layer consisting essentially of rivastigmine free base; PLASTOID ^™ B (Evonik); and DURO-TAK ^™ 87-235A (Henkel); and (b) substantially Provided is a rivastigmine-containing patch comprising a double layer of a skin adhesive layer consisting only of BIO-PSA ^™ 7-4302 (manufactured by Dow Corning).

The present invention also provides
(A) a drug adhesion layer consisting essentially only of the solid content of rivastigmine free base; PLASTOID ^™ B (manufactured by Evonik); and DURO-TAK ^™ 87-2510 (manufactured by Henkel), and (b) substantially In particular, the present invention provides a rivastigmine-containing patch comprising a double layer of a skin adhesive layer composed only of a solid content of BIO-PSA ^™ 7-4302 (manufactured by Dow Corning).

  Here, “substantially” means that other components (especially antioxidants such as tocopherol) other than the mentioned components are contained in an amount of 1% by weight or less, preferably 0.5% by weight or less. , More desirably 0.1% by weight or less, and most desirably 0.05% by weight or less.

In the rivastigmine-containing patch according to the present invention, the drug adhesive layer comprises 25 to 35% by weight of rivastigmine free base relative to the total weight of the drug adhesive layer; a copolymer of butyl methacrylate and methyl methacrylate (preferably PLASTOID ^™ B). 16-24% by weight; and a random copolymer of 58-66 parts by weight of 2-ethylhexyl acrylate, 28-36 parts by weight of methyl acrylate, and 4-8 parts by weight of acrylic acid (preferably DURO-TAK ^™ 87-235A solid Min) consisting of 45-55% by weight, and the skin adhesive layer has a weight after drying of dimethylsiloxane-treated trimethylated silica (preferably BIO-PSA ^™ 7-4302 solids) 27-33 mg / cm ² ( More desirably 30 mg / c Is produced at a dose of ²⁾ it is desirable.

The present invention also provides:
(A) Rivastigmine free base; copolymer of butyl methacrylate and methyl methacrylate (preferably PLASTOID ^™ B (manufactured by Evonik)); 58 to 66 parts by weight of 2-ethylhexyl acrylate, 28 to 36 parts by weight of methyl acrylate , And a random copolymer of 4 to 8 parts by weight of acrylic acid (preferably DURO-TAK ^™ 87-235A (manufactured by Henkel)), and the solvent, libastigmine release relative to the total weight of the drug adhesive layer after drying 25-35% by weight base; 16-24% by weight copolymer of butyl methacrylate and methyl methacrylate; and 58-66 parts by weight 2-ethylhexyl acrylate, 28-36 parts by weight methyl acrylate, and 4-8 parts by weight acrylic acid Random copolymer 45 of Mixing the ingredients to make up to 55% by weight and forming a drug-forming layer with the mixture, and (b) dimethylsiloxane treated trimethylated silica (preferably BIO-PSA ^™ 7-4302 by weight after drying) A method for producing a rivastigmine free base-containing patch comprising the step of producing a skin adhesive layer so as to have a solid content of 27 to 33 mg / cm ² (more desirably 30 mg / cm ² ) is provided.

  In the production method according to the present invention, the step (b) may be performed after the step (a), may be performed before the step (a), or may be performed simultaneously with the step (a).

  In the case of a patch manufactured in this way, the presence and mixing ratio of other components present in the drug adhesive layer (drug-containing layer) / skin adhesive layer has a very serious influence on the release of the main component. Therefore, the contents of additives and components must be finely adjusted.

  The administration dose of the rivastigmine patch according to the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health condition, disease severity, and the like. A commercially available transdermal rivastigmine product is applied to the skin 9 to 18 mg once a day for the treatment of Alzheimer-type dementia, Parkinson's disease dementia and the like.

  The rivastigmine patch according to the present invention is excellent in stability and exhibits an appropriate release pattern.

It is a skin permeability measurement result in the experiment for selecting the ratio of an adhesive. It is a skin permeability measurement result in the experiment for setting the prescription of a skin adhesion layer. It is a skin permeability measurement result in a polymer selection study. It is a skin permeability measurement result using a membrane of the most desirable formulation according to the present invention. It is a skin permeability measurement result using human cadaver skin of the most desirable formulation according to the present invention.

  The present invention will be described in detail below with reference to examples and the like so as to facilitate understanding of the present invention. However, the embodiments according to the present invention can be modified in many other forms, and the scope of the present invention should not be construed to be limited by the following embodiments. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the concept of the invention to those skilled in the art.

<Example 1> Research on adhesive (adhesive) In order to develop the rivastigmine base which is the main component of a rivastigmine patch as a patch agent, the experiment which selects a suitable adhesive was conducted.

Selection of pressure-sensitive adhesive In order to select a pressure-sensitive adhesive suitable for the manufacture of rivastigmine patches, the appearance, miscibility, and compatibility were confirmed by mixing rivastigmine base with various pressure-sensitive adhesives.

  For the compatibility test, the following ten types of pressure-sensitive adhesives were selected as candidate substances in consideration of the type of polymer contained in the pressure-sensitive adhesive composition, functional groups, presence / absence of crosslinking, and solvent in the composition. Table 2 below shows information on the selected adhesive.

  In Table 2, EA means ethyl acetate, IPA means 2-propanol, MeOH means methanol, and EtOH means ethanol.

  Candidate materials for adhesives include polymers of acrylic series or acrylate-vinyl acetate series, and have no functional group, or have a hydroxyl group or a carboxyl group. Differences in compatibility with and without cross-linking agents were also evaluated as important factors. The appearance and miscibility of the pressure-sensitive adhesive are shown in Table 3 below.

  As shown in Table 3, after observing the properties of the mixture of the main component and the pressure-sensitive adhesive for 2 weeks, the pressure-sensitive adhesive that was initially colorless or light yellow changed from colorless or light yellow to yellow It was observed that the color changed to brown. It was observed that the property changed to yellow at 87-202A, and the property changed to brown at 87-2852, 87-2516, and 87-2052. Thus, it was confirmed that the pressure-sensitive adhesive having a severe property change is a pressure-sensitive adhesive having a crosslinking agent in common. In the case of 87-4287, a change from colorless to slightly yellow was observed. As a result of observing the miscibility between the main component and the pressure-sensitive adhesive, the miscibility between the main component and the pressure-sensitive adhesive was good in all the pressure-sensitive adhesives except 87-4098.

  From the above experimental results, it was found that suitable adhesives for mixing with the main component of the rivastigmine patch were No. 3 and No. 6 adhesives, 87-2510 and 87-235A adhesives. When the amount of the flexible material generated by the two adhesives was compared, the mixture of 87-235A and the main component was more stable. Therefore, 87-235A was selected as the adhesive used in the development of the rivastigmine patch according to the present invention, and the following research was conducted.

Next, in the prescription study of rivastigmine patch preparation, the 87-235A adhesive selected in the pre-formulation research process has the same permeability as Exelon ^TM as a control drug Tried to select a prescription. Rivastigmine base is a liquid phase at room temperature, and when developing as a patch, if the main component that is the liquid phase is 30% by weight or more of the formulation of the drug-containing layer, it is necessary to add a thickening polymer. For this reason, it was decided to add a polymer (PLASTOID B) that is compatible with the main component. Therefore, in order to set the ratio of the main component having the same permeability as that of the control drug, the ratio of the main component and the polymer is fixed at a weight ratio of 3: 2, the amount of the adhesive is adjusted, and the adhesive layer An experiment was conducted to set the ratio. With reference to the results of the pre-formulation study, Durotak 87-235A was used as the adhesive and PLASTOID B was used as the polymer. Candidate prescriptions in which the ratio between the main component and the adhesive is changed are as follows. Polymer ratio optimization was done in the next research phase.

A patch was manufactured according to the above formulation and a skin permeability test was conducted. In the production of the patch, the main component was 18 mg per 10 cm ^{2 in} all formulations. The skin permeability test conditions were as follows, and the experimental results are shown in FIG.

As shown in FIG. 1, the result was obtained that the higher the concentration of the main component, the higher the transmittance. The concentration of the main component to have a permeation rate (for example, flux) equivalent to the control drug Exelon ^™ was 15 to 30% by weight. Additional studies will be conducted to adjust the ratio of the main components to ensure a formulation that shows the same permeability as the control drug, taking into consideration the adhesion of the adhesive layer and the occurrence of cold flow. The study was conducted in a direction to take into account changes.

Adhesion layer adhesion and cold flow evaluation The rivastigmine patch formulation prepared as described above was applied to human skin for 24 hours to evaluate adhesion layer adhesion and cold flow. A phenomenon was observed in which the patch slipped and moved from the sticking site due to the poor nature, resulting in dark rings. This is because the rivastigmine base, which is the main component of the rivastigmine patch, is a liquid phase substance at room temperature, and when the liquid phase main component is mixed with the adhesive, the patch reduces the adhesive strength of the adhesive. It is thought that a dark ring is generated by sliding from the adhesive site of the skin. In order to improve it, the skin adhesive layer is manufactured with the main component and other series of adhesives that are not mixed with the acrylic adhesive, and a double layer formulation that overlaps the drug layer containing the drug is developed to solve the above problems. Tried.

Example 2 Study of Skin Adhesive Layer Selection of Adhesive for Skin Adhesive Layer The skin adhesive layer was studied using the formulation of the drug adhesive layer selected in the above study of the drug-containing layer. Since the skin adhesive layer of the rivastigmine patch preparation must maintain a separate layer from the drug adhesive layer, it should not be mixed with the acrylic adhesive used as the adhesive for the drug adhesive layer. In addition, if the main component of the rivastigmine patch is miscible with the skin adhesive layer, the drug in the drug adhesive layer may move to the skin adhesive layer due to the concentration gradient and affect the adhesive strength of the skin adhesive layer. Therefore, the main component and the adhesive of the skin adhesive layer must be easily mixed. In order to select a pressure-sensitive adhesive that satisfies the above conditions, the miscibility of the silicone-based pressure-sensitive adhesive, the rubber-based pressure-sensitive adhesive, and the polyisobutylene-based pressure-sensitive adhesive with the main components was evaluated. As a result of observing the miscibility of the adhesive and the main component, the rubber-based adhesive and the polyisobutylene-based adhesive have good miscibility with the main component, and the silicone adhesive has poor miscibility with the main component. The phenomenon of separation of layers occurred. Each pressure-sensitive adhesive was applied to a film so that the thickness after drying was 50 μm, and then adhered to human skin for 24 hours to evaluate the occurrence of cold flow. The degree of occurrence of dark ring due to cold flow was digitized from 0 to 5, and the average was obtained and evaluated, and an experiment was conducted by attaching a patch to the upper eyelid site for 10 people. Evaluation items evaluated the adhesive state of the patch, the degree of occurrence of dark rings, and the strength of adhesive force. The evaluation criteria are as follows. Table 6 below shows the scoring criteria for the adhesive strength evaluation items of the adhesive.

  The degree of dark ring generation due to the miscibility and adhesive strength of the adhesive is shown in Table 7 below.

  As a result of the evaluation, dark ring of the same level or lower than that of the control drug was observed in the silicone pressure-sensitive adhesive, and dark ring equivalent to or higher than that of the existing acrylic pressure-sensitive adhesive was generated in the rubber-based adhesive and polyisobutylene-based adhesive. I knew that to do.

  Based on the above experimental results, rubber adhesive and polyisobutylene adhesive are miscible with the main components of acrylic adhesive and rivastigmine patch, so they cannot be used as a skin adhesive layer and are cold. It has been found that an acrylic adhesive and a silicone adhesive that is not mixed with the main component must be used as the skin adhesive layer to minimize flow.

Prescription setting for skin adhesive layer Among the double-layer formulation of rivastigmine patch preparation, the skin adhesive layer (second layer) using silicone adhesive acts as a barrier between the skin and drug adhesive layer. , Reduce the permeability of the main component. Therefore, its thickness was expected to have an important effect on skin permeability. Therefore, a double layer was produced by changing the amount of the adhesive per unit area, and the skin permeability of each was observed. As the drug adhesive layer, the I100526-2 formulation used in the study of the drug-containing layer (first layer) was used, and the skin adhesive layer coated with three types of silicone adhesives in various thicknesses was layered on the control drug. A study was conducted to ensure the same skin permeability.

The thickness of the skin adhesive layer was adjusted by the weight of the silicone adhesive per unit area, and when having a weight of 30 mg at 10 cm ² , the thickness of the skin adhesive layer was 30 μm. Furthermore, when having a weight of 60mg in 10 cm ^2, the thickness of the skin adhesive layer was confirmed to be 60 um. The 48 hour skin permeation results of the formulation are shown in FIG.

As shown in FIG. 2, it was found that the thicker the skin adhesive layer, the thicker the barrier between the skin and the drug and the lower the drug permeability. Formulations having the same transmittance as the control drug were those using Bio PSA 7-4202 30 mg / 10 cm ² and Bio PSA 7-4302 30 mg / 10 cm ² as the skin adhesive layer.

<Example 3> Research of polymer When manufacturing a rivastigmine patch, the rivastigmine base, which is the main component, is in a liquid phase, so when applied to the patch, a constant thickness cannot be maintained. A flowing phenomenon occurred. If such a phenomenon occurs, the coating thickness becomes unstable, and it becomes difficult to keep the content after drying constant. Therefore, in order to ensure the viscosity required for the application of the mixture, it was decided to include in the formulation a polymer to be applied as a thickener and a film former. In order to select a suitable polymer for the production of rivastigmine patches, the compatibility of rivastigmine base with various polymers was evaluated and the above mentioned that PLASTOID B is suitable in terms of appearance, miscibility and compatibility. Confirmed in the study. An experiment was conducted using the selected PLASTOID B to set a suitable polymer ratio in the formulation.

In order to study the formulation of rivastigmine patch formulation, an attempt was made to select a formulation with a permeability equivalent to that of the control drug using the polymer selected in the pre-formulation research process. The rivastigmine base, which is the main component of the rivastigmine patch, is a liquid phase at room temperature, and when the main component in the formulation is 30% by weight or more, it is necessary to add a thickening polymer. It was decided to add a polymer (PLASTOID B) that ensured compatibility. In order to set the ratio of the polymer having the same permeability as that of the control drug, the ratio of the main component of the drug-containing layer (first layer) to the pressure-sensitive adhesive is fixed to 3: 5 according to the research result of the pressure-sensitive adhesive ratio setting. Experiments were conducted to set the ratio of the polymer by adjusting the amount of the polymer to 10 to 30% by weight. At this time, the preselected Bio PSA 7-4302 30 mg / 10 cm ² (weight basis after drying) was used as the skin adhesive layer (second layer). Candidate formulations with varying polymer ratios are as follows.

Patches were produced with the above formulation and tested for skin permeability. Patches were prepared so that the main component per 10 cm ² was 18 mg in all formulations, and the difference in content depending on the ratio of the polymer was corrected after confirming the content to the permeation rate (eg, flux) test results. Reflected. When the polymer ratio was 30% by weight, the viscosity of the mixed solution was so high that the properties at the time of application were poor, so a formulation with a ratio higher than 30% by weight was not produced. The results of observation of skin permeability for 48 hours are shown in FIG.

  As shown in FIG. 3, it was found that the higher the polymer content, the lower the transmittance. This is thought to be because the viscosity increases with increasing polymer content, hindering drug diffusion and hindering drug release. Therefore, it was confirmed that the prescription (I100614-2) containing 20% polymer in the prescription showed the same permeability as the control drug.

<Example 4> Selection of Final Formulation As a result of pharmacological research on rivastigmine patches, the most preferable formulation for producing rivastigmine-containing patches according to the present invention selected through the above examples is shown in the following table. It seems to be.

  A rivastigmine patch was produced with the selected final formulation, and the results of comparative observation of the permeation rate (for example, flux) between the patch of the present invention and the control drug on membrane and human cadaver skin for 72 hours are shown in FIG. Brain) and 5 (human cadaver skin).

  As shown in FIGS. 4 and 5, it was confirmed that the rivastigmine patch formulation of the present invention selected through pharmacological studies showed the same permeability as the control drug in membrane and human cadaver skin. .

<Example 5> Packaging condition selection test A severe stability test was conducted to select packaging conditions necessary for stable storage of the Rivastigmine patch. The packaging materials used for the harsh tests were aluminum pouch packaging and sachet packaging containing polyacrylonitrile material.

  Specifically, in order to evaluate the effect of atmospheric oxygen on the stability of the formulation, the packaging conditions are divided into atmospheric packaging and nitrogen packaging, and the stability of the rivastigmine patch according to the present invention under severe conditions is determined. evaluated. The results are shown in Table 11.

  As shown in the above results, the increase in the flexible material of the rivastigmine patch was the smallest when nitrogen packaging was performed, and from this result, conditions suitable for packaging of the rivastigmine patch could be confirmed.

Claims (10)

(A) rivastigmine free base; a copolymer of butyl methacrylate and methyl methacrylate; and a drug adhesive layer produced using an adhesive;
(B) In a rivastigmine-containing patch comprising a double layer of a skin adhesive layer containing a silicone adhesive,
A rivastig comprising a random copolymer of 58 to 66 parts by weight of 2-ethylhexyl acrylate, 28 to 36 parts by weight of methyl acrylate, and 4 to 8 parts by weight of acrylic acid as an adhesive for the drug adhesive layer. Min patch. The rivastigmine patch according to claim 1, wherein DURO-TAK ^™ 87-235A (manufactured by Henkel) is used as an adhesive for the drug adhesive layer.   The copolymer of butyl methacrylate and methyl methacrylate is a random copolymer of butyl methacrylate and methyl methacrylate, and has a weight average molecular weight of 130,000 to 170,000 g / mol. Rivastigmine patch as described in. The rivastigmine patch according to claim 3, wherein the copolymer of butyl methacrylate and methyl methacrylate is PLASTOID ^™ B (manufactured by Evonik).   The rivastigmine patch according to claim 1, wherein the silicone adhesive is dimethylsiloxane-treated trimethylated silica. The rivastigmine patch according to claim 5, wherein the silicone pressure-sensitive adhesive is derived from BIO-PSA ^TM 7-4302 (manufactured by Dow Corning). The rivastigmine patch according to claim 6, wherein the BIO-PSA ^TM 7-4302 is used in a capacity of 27 to 33 mg / 10 cm ^{2 based} on the weight after drying. (A) rivastigmine free base; PLASTOID ^™ B (manufactured by Evonik); DURO-TAK ^™ 87-235A (manufactured by Henkel); and a drug adhesive layer produced selectively using only a solvent;
(B) A rivastigmine-containing patch comprising a bilayer of BIO-PSA ^™ 7-4302 (manufactured by Dow Corning); and optionally a skin adhesive layer produced using only a solvent. (A) rivastigmine free base; PLASTOID ^™ B (manufactured by Evonik); DURO-TAK ^™ 87-2510 (manufactured by Henkel); and a drug adhesive layer produced selectively using only a solvent;
(B) A rivastigmine-containing patch comprising a bilayer of BIO-PSA ^™ 7-4302 (manufactured by Dow Corning); and optionally a skin adhesive layer produced using only a solvent.   A rivastigmine patch product, wherein the patch according to any one of claims 1 to 9 is packed with nitrogen.

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